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Key Words: chemotherapy, gastrointestinal stromal tumor, imatinib mesylate (Gleevec™). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Gleevec, a new cancer drug approved on May 10, 2001, for the treatment of some types of leukemia (see press release), now appears also to work in a rare type of cancer called gastrointestinal stromal tumor (GIST). [Editor's Note: On Feb. 1, 2002, the U.S. Food and Drug Administration approved Gleevec for the treatment of GIST; see a summary of the approval.] Two reports presented from early clinical trials of the drug, also called STI571, were presented at the 2001 annual meeting of the American Society of Clinical Oncology in San Francisco on May 14.

Charles D. Blanke, M.D., from the Oregon University Health Sciences Center, presented the first report on behalf of the GIST Working Group. In this phase II clinical trial, researchers randomly assigned 148 patients to receive either intermediate or high doses of Gleevec, which is taken in the form of a pill. Patients who experienced growth of their cancer on the lower dose were moved up to the higher dose.

Over all, 85 percent of patients had tumors that responded to Gleevec. Partial responses --some shrinkage of the tumors -- were seen in 59 percent of patients, while another 26 percent had tumors that stopped growing after taking the drug.

As demonstrated in previous Gleevec studies, side effects were tolerable. The most common side effects in the GIST Working Group trial were swelling of the legs and eyes and tumor bleeding, which may be a sign that the tumor is responding to treatment.

Other side effects included liver damage, low white blood cell counts and infections. While 21 percent of patients experienced severe to life-threatening toxicities, no person in the study died from the treatment.

Because the drug appeared so promising early in the trial, the study -- originally planned to include only 36 patients -- was increased to 150 patients to allow more people access to the drug. All patients had tumors that could not be removed by surgery; in addition, the tumors had to have a particular gene called KIT. Gleevec is thought to work by blocking the KIT pathway, which then stops the cancer from growing. Patients with certain changes in the KIT gene were more likely to respond to Gleevec.

Gleevec represents a new approach to cancer treatment, one that targets the unique genetic defects present in tumors. This type of approach will "change the way we treat cancer," declared Blanke. "[M]olecularly targeted therapy should be a recurrent theme in future research."

Researchers from Europe were equally enthusiastic about the early clinical trial results of GIST. Allan T. van Oosterom, M.D., Ph.D., from the Department of Oncology of UZ Gasthuisberg KULeuven in Belgium, led a smaller, phase I clinical trial, designed to test the optimal dose of Gleevec in GIST. The study, coordinated through the European Organization for Research and Treatment of Cancer, enrolled 40 patients with GIST. [Editor's note: The results from this phase I trial were subsequently published in the Sept. 2002 issue of the European Journal of Cancer. See the journal's abstract.]

Similar side effects were seen in this trial, including nausea, vomiting, swelling, rash and low blood counts. While most of these side effects lessened after about six weeks of treatment, low blood counts occasionally appeared for the first time two months into treatment. These low blood counts improved after temporarily stopping the drug.

Patients in the European trial received varying doses of Gleevec and were given the drug for at least one year, or until the tumors started growing again. Overall, 69 percent of the GIST patients responded to the drug (15 out of 36). While the researchers did not report any complete responses, they did note that several patients' tumors appeared to totally disappear on a special type of scan that measures tumor activity. Van Oosterom heralded this research as a "new era" for cancer therapy.

Approximately 5,000 cases of GIST are diagnosed in the U.S. each year, although scientists noted that the actual number might be higher. Prognosis tends to be poor, even for early tumors that can be removed by surgery. Treatment with traditional chemotherapy and radiation treatment usually has little effect on GIST.

Clearly beneficial responses like those in the two GIST trials described here are rarely seen in early clinical trials. In a discussion led by Charles Sawyers, M.D., from the UCLA Jonsson Cancer Center in Los Angeles, the enthusiasm continued.

At the same time, Sawyers issued similar cautions as the two lead researchers -- namely, that both trials have only followed patients for several months. Long-term follow-up will determine if these dramatic early responses last, he said. Additionally, the drug, while clearly less toxic and much better than traditional chemotherapy or radiation treatments, still has side effects.

The other caveat is that genetic mutations in the tumor appear to predict which tumors will respond to the drug. Discussants said that this type of testing should happen before any patient receives Gleevec for GIST.

All of the scientists commented that the optimal treatment with Gleevec remains to be clarified; they urged continued patient enrollment in controlled clinical trials designed to answer these questions. Current studies in GIST, brain tumors and leukemia are ongoing in the U.S. and around the world.

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